Age-related macular degeneration (AMD) is the most common cause of blindness in developed countries, particularly in people older than 60 years. There is no treatment for the most prevalent dry form of AMD which affects 90% of patients. It is estimated that 62.9 million individuals worldwide currently have dry AMD. Age-dependent accumulation of cytotoxic lipofuscin in the RPE matches the age-related increase in dry AMD prevalence implicating lipofuscin as a significant factor in pathogenesis of dry AMD. The major cytotoxic components of retinal lipofuscin are pyridinium bisretinoids. Lipofuscin bisretinoids exert a variety of toxic effects on normal RPE. In addition to direct toxicity, lipofuscin bisretinoids induce complement system dysregulation in the retina. Non-enzymatic synthesis of lipofuscin bisretinoids in the dry AMD retina is fueled by the influx of all-trans-retinol from circulation to the retina. It was suggested that partial pharmacological reduction of serum retinol represents a sound treatment strategy for dry AMD. Formation of the tertiary Retinol- Binding Protein 4 (RBP4)-transthyretin (TTR)-retinol complex in the serum is required for the uptake of retinol from circulation to the retina. Without interacting with TTR, RBP4-retinol is rapidly cleared from circulation through glomerular filtration due to a small size of the RBP4-retinol complex. Selective RBP4 antagonists are known to antagonize the retinol-dependent RBP4-TTR interaction inducing the desired lowering in serum RBP4 and inhibition of lipofuscin bisretinoid synthesis in the eye. However, it is thought that complexation of TTR with RBP4 in circulation stabilizes tetrameric TTR which slows TTR amyloid formation. Selective RBP4 antagonists would release TTR tetramers from the circulating RBP4-TTR complex which may facilitate TTR amyloidogenesis. Selective RBP4 antagonists may be counter-indicated for a significant number of dry AMD patients who may be prone to developing transthyretin amyloidosis. Senile systemic amyloidosis (SSA) affects approximately 25% of patients over the age of 80 and is derived from aggregation of wild-type transthyretin (TTR) in various organs and tissues. This type of TTR amyloidosis involves the heart and results in heart failure, atrial fibrillation, and may lead to death. Based on the high population frequency of SSA and dry AMD significant comorbidity between the two conditions is expected. We identified a new class of bisretinoid- reducing compounds which comprises a group of dual RBP4/TTR ligands. The new class lacks a potential liability of selective RBP4 antagonists as these compounds can act as kinetic stabilizers of the released TTR tetramers. We identified a proprietary RBP4/TTR ligand, CU163, as a lead compound that requires additional optimization. The studies outlined in this proposal seek to conduct medicinal chemistry optimization of the lead compound using a battery of primary, secondary and counterscreen assays (Specific Aim 1), and to perform evaluation of the optimized RBP4/TTR ligands in in vivo efficacy experiments (Specific Aim 2).